Previous treatments for bronchial bleeding or hemoptysis comprise surgical and medical approaches. Among surgical approaches, local lesions can sometimes be treated by excision or cauterization via bronchoscopy, but this applies only to restricted numbers and classes of lesions. Among medical approaches, the most common is the systemic administration of blood platelets and/or blood coagulation factors, of which the patient may have a congenital or acquired deficiency, and/or the systemic administration of inhibitors of fibrinolytic (clot-dissolving) mechanisms. The latter include tranexamic acid, which inhibits the conversion of plasminogen to the fibrinolytic enzyme plasmin, and aprotinin, which inactivates fibrinolytic enzymes. The disadvantage of these medical approaches is that their effect is often inadequate to arrest the local bronchial or alveolar bleeding, especially if this is caused by a combination of one or more local lesions and a generalized deficiency of one or more hemostatic mechanisms or due to an affection of the alveolo-capillary membrane either of primary, unknown etiology or secondary to an identifiable systemic disease or condition, such as bone marrow transplantation, chemotherapy, systemic autoimmune disease or infection. The inhibition of fibrinolysis can only arrest bleeding if the hemostatic mechanisms are adequate to form a blood clot in the first place. Bronchial or diffuse alveolar bleeding or hemoptysis is typically a medical emergency, in which rapid arrest of bleeding is required, often allowing insufficient time to identify the underlying causes with certainty, and in which treatment of the underlying disease is too retarded in comparison with the acute life-threatening hemorrhage. Medical treatments are therefore often given speculatively and without certainty of their efficacy.
Various methods of airway administration of substances intended to exert a therapeutic effect either locally or systemically or both have been the subject of both publications and patent applications. For example U.S. Pat. No. 3,920,845 discloses methods for treating allergic conditions with daily doses of 2-nitroindan-1,3-dione administered orally, parenterally or by insufflation. Methods for treating inflammation, allergic reactions and/or asthma via inhalation therapies are also disclosed in U.S. Patents and U.S. Pat. Nos. 5,980,865, 6,193,957, 6,497,877, and U.S. 2003/0195141 and U.S. Pat. No. 5,690,910 discloses intrabronchial administration of therapeutic agents for treatment of antigen-induced asthma. U.S. Pat. No. 5,427,797 discloses a method for administering nitric oxide by the inhalation route to prevent or treat blood platelet aggregation. U.S. Pat. No. 5,096,916 discloses administration of an imidazoline compound, which is a vasodilator and an alpha-adrenergic blocking agent, by inhalation for the treatment of symptoms of chronic obstructive pulmonary disease. US 2004/0265238 discloses an inhalable formulation of a hypertension reducing agent for treatment of pulmonary hypertension.
These patents serve to indicate the feasibility of drug delivery by airway administration, and thus their teachings are incorporated herein by reference in their entirety. However, the purpose of airway delivery of the administered substance(s) in the majority of these teachings has not been to arrest bleeding into the airway.
Gong et al. (U.S. 2005/0008580) disclose a method of treating hemophilia by the inhalation of aerosolized factor XI (FIX) of certain chemical characteristics and particle size, and the potential administration of factor VIII (factor VIII) in the same way is also disclosed, though not the subject of any claim. The purpose of this administration of FIX or factor VIII is to replace regular systemic administration of these factors in the long-term treatment of hemophilia, not to arrest bleeding into the airway.
Thrombin alone or thrombin together with fibrinogen has been applied intrabronchially by means of a bronchoscope to treat localized bleeding in the bronchial tree (Kinoshita et al., 1982; Tsukamoto et al., 1989; de Gracia et al., 1995; Saito et al., 1998; Hosoda et al., 2001; de Gracia et al., 2003). However, these results do not have predictive value for other coagulation factors that act at en earlier stage of the coagulation cascade. In the cited publications, thrombin and fibrinogen have been used as a specific surgical fibrin-forming “glue” to treat only those localized bleeding lesions that are accessible to the bronchoscope, and not bleeding from a wider area of the bronchoalveolar tree. On the other hand, general instillation or inhalation of thrombin and fibrinogen has not proved successful, incurring a risk of airway obstruction. It is therefore of therapeutic interest to use other coagulation factors acting at an earlier stage of the coagulation cascade and thus subject to local regulating influences to avoid an undesirably heavy deposition of fibrin glue in large parts of the airway. The present invention concerns the administration via the airway of other activated coagulant factors to treat both diffuse and localized bleeding in the airways.